Treatment Methods and Early Neurologic Improvement After Endovascular Treatment of Tandem Occlusions in Acute Ischemic Stroke

Background and Purpose: A tandem occlusion of the intracranial circulation and the extracranial carotid artery (ICA) occurs in 10–20% of all strokes based on large vessel occlusion (LVO). The optimal treatment strategy for those patients is unknown. We report our management strategy and the outcome in these patients in a large single-center cohort.Materials and Methods: We retrospectively identified and analyzed all patients treated by Mechanical Thrombectomy (MT) for an intracranial LVO associated with an occlusion of the extracranial ICA between April 2009 and May 2016 (163/1,645, 9.9%). The following data was collected: Recanalization rate, occurrence of symptomatic intracranial hemorrhage (sICH), clinical result according to the early neurological improvement (ENI, NIHSS score improvement of ≥8 points after 24 h or NIHSS score of 0 or 1 after 3 days) and functional outcome and mortality during long term follow up. Secondary endpoints were the patency of the internal carotid artery at 24 h. Patient demographics and anti-aggregation regimen were recorded as co-variables.Results: 163/1,645 (9.9%) MT patients had a tandem occlusion. All thrombectomy procedures were performed with stent retrievers. PTA with or without additional placement of a stent was performed in 149 vs. 14 patients. The overall rate of TICI IIB/III recanalization was 91.4%. An early neurological improvement was found in 79 of 163 patients (48.4%), 51% (76/149) in the stent group and 21% (3/14) in the non stent group. 120/163 patients (73.6%) had a long term favorable outcome (mRS 0–2). The ICA re-occlusion rate at 24 h was 5.4% (8/149) in the stent group and 42% (6/14) in the non stent group. The rate of symptomatic hemorrhage was 4.9%.The regression analysis showed that only younger age (p = 0.002) and shorter recanalization times (p = 0.017) were associated with good outcome.Conclusion: Stent-PTA of the ICA in addition to MT with a stent retriever was safe and effective in tandem occlusion of the anterior brain circulation. PTA and MT without stenting in tandem lesions showed a higher early re-occlusion rate and lower rate of early neurological improvement. The technical approach should aim for the fastest possible recanalization of the intracranial vessels, either with stenting first or last

Intracranial Stenting After Failed Thrombectomy in Patients With Moderately Severe Stroke: A Multicenter Cohort Study

Background and Purpose: Recently, acute intracranial stenting (ICS) has gained more interest as a potential bailout strategy for large vessel occlusions (LVO) that are refractory to thrombectomy. However, there are currently no reports on ICS in patients with moderately severe stroke discussing the question if implementing a permanent stent is feasible and leads to improved recanalization after failed thrombectomy. Methods: We analyzed a large multicenter database of patients receiving ICS for anterior circulation LVO after failed thrombectomy. Inclusion criteria were defined as: Moderately severe stroke (National Institute Health Stroke Scale (NIHSS) ≤9 on admission), anterior circulation LVO, acute ICS after failed stent retriever MT. Primary endpoint was the rate of improved successful recanalization after ICS defined as a modified Thrombolysis In cerebral Infarction (mTICI) score≥2b. Favorable neurological outcome was defined as an early neurological improvement (ENI) of 4 points or reaching 0 with respect to baseline NIHSS. Results: Forty-one patients met the inclusion criteria. A median of 2 retrievals were performed (IQR 1–4) prior decision-making for ICS. ICS led in 90.2% (37/41) of cases to a final mTICI≥2b with significant improvement (p < 0.001) after the last retrieval attempt. The median NIHSS decreased (p = 0.178) from 7 (IQR 3.5–8) on admission to 2.5 (IQR 0–8.25) at discharge. ENI was observed in 47.4% (18/38). sICH occurred in 4.8% (2/41). Conclusion: ICS after failed thrombectomy appears to effectively improve recanalization rates in patients with moderately severe strokes. Thus, ICS should be considered also for patients with baseline NIHSS ≤9 if thrombectomy fails

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

HapMap imputed genome-wide association studies (GWAS) have revealed &gt;50 loci at which common variants with minor allele frequency &gt;5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value &lt; 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR &lt; 0.05) genes and 127 significantly (FDR &lt; 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4-2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in genera

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

HapMap imputed genome-wide association studies (GWAS) have revealed > 50 loci at which common variants with minor allele frequency > 5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 x 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until wholegenome sequencing becomes feasible in large samples

1000 Genomes-based metaanalysis identifies 10 novel loci for kidney function

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-Analysis of kidney function based on the estimated glomerular filtration rate (EGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, wh

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Experimentelle Magnetresonanzangiographie unter Verwendung von kontrastangehobenen und flußrichtungssensitiven Meßtechniken

Purpose: 1.Evaluation and further development of a new flow sensitive MR protocol in a pig model. 2.To prove the value of blood pool contrast agents in MR coronary angiography using an established ultrafast two dimensional gradient echo sequence. Material and methods: After verification and modification of the MR sequence sensitive to flow direction in a plastic tube model the sequence was performed in 8 pigs using a 1.5 Tesla MRI-Scanner (Philips Gyroscan ACS NT). The MR angiography protocol was applied in two-dimensional spin-echo- and echoplnar (EPI) technique with variable located excitation- and refocussing HF-pulses in the direction of slice-selection to obtain selective imaging of arterious and venous structures. In systematic studies several parameters were changed as the repetition time, the echo time, the slice thickness, flip angle and the sizes of excitating and refocussing HF-pulses. At another day the same animals underwent a further study: an ultrafast two-dimensional T1-weighted gradient echo protocol for bright-blood imaging of coronary vessels was performed with application of a gadolinium-based blood-pool contrast agent ( Gadomer 17, Schering AG) in dose of 0.2 mmol per kilogram of body weight. During the studies the measurement protocol was improved. Results and discussion: 1. Using local deviated HF-pulses in spin-echo sequences selective imaging of arteries and veins is possible without contrast agent only due to flow direction. The protocol is more sufficient in the imaging of veins, imaging of arteries is not satisfying due to low signal- to noise ratios and severe ghosting artifacts. 2. In coronary MRA higher signal levels in proximal coronary anatomy can be obtained by using blood pool contrast agents, a further depiction of the distal and small coronary vessels does not occur